Monoclonal antibody therapy is now an accepted component of standard treatment of lymphoma. Despite impressive recent progress, there is clearly room for improvement based on advances in our understanding of mechanism of action. Class II MHC is an attractive antigen for monoclonal antibody-based therapy based on its role in B-cell signaling and in development of an active immune response. Hu1D10 is an anti- HLA-DR antibody that can lead to apoptosis, and has signaling effects are different than those seen with anti-CD20. A phase I trial of Hu1D10 demonstrated gradual but high-grade clinical responses in 4 of 8 subjects with follicular lymphoma despite rapid clearance of the moAb from the circulation. Correlative data in one subject suggests the possibility that therapy with this moAb induced development of an active anti- lymphoma humoral immune response. The overriding hypothesis of the current proposal, based on this preliminary data, is that The anti-tumor effect of the Hu1D10 anti-HLA-Dr antibody is due to its ability to induce development of an active anti-tumor immune response. Induction of tumor cell apoptosis, and alteration of the function of antigen presenting cells may also play a role in the observed clinical findings. Three specific aims will explore the ability of the Hu1D1- to induce apoptosis and impact on development of an active anti-tumor response both in vitro and in patients. Aim #1 is designed to determine whether the anti-HLA-DR antibody Hu1D10 induces apoptosis of primary follicular lymphoma cells. Aim #2 will explore whether this antibody binds to benign antigen presenting cells and alters their antigen presenting capabilities. Aim #32 will determine whether clinical therapy with Hu1D10 induces an active anti-lymphoma immune response. Successful completion of these studies will have a major impact on our understanding of the potential of therapy directed against class II MHC, and will contribute to our understanding of cancer immunotherapy in general.